This case-control study investigated the cerebellar anatomic and functional changes across three different cognitive status, including the NC, aMCI, and AD group. The strength of cerebellar FC with cerebral cortical areas were different among three groups, and it correlated with cognitive function in AD and aMCI.
The weakened FC was found between the left VIIb and contralateral precuneus and cuneus, and between left IX and bilateral precuneus and cuneus in AD. Precuneus is one of the core regions of default mode network (DMN). Aβ accumulation preferentially starts in several of the core regions of the DMN, including the precuneus at the early stage of AD. From the perspective of clinical symptoms, the DMN has been found to be related to episodic memory in AD [25, 27]. Failure to detect the correlation with the cognitive performance, especially with the memory, could be due to the restricted range of this dependent variable in our aMCI cohort. The correlation with memory was found between left IX and contralateral precuneus in AD group (Supplementary Table 2).
Compared to NC, the aMCI and AD group showed weaker FC of the left Crus I correlated with frontal lobe (bilateral DLPFC, left ACC and right IFG), while right Crus I with occipital and temporal lobule (bilateral FG, left ASC and right MTG). The role of Crus I in working memory, planning and organization have been highlighted by functional imaging studies. In addition, the role of DLPFC in executive function had been clearly established. This is consistent with our result that the FC between left Crus I and bilateral DLPFC correlated with execution. Previous fMRI also demonstrated the crossed cerebro-cerebellar projections, language is heavily right lateralized and visuospatial function left lateralized. Interestingly, in this study, we found similar lateralization in Crus I, as the FC of left Crus I connected with the execution and visuospatial function, and right Crus I connected with the memory and language.
Crossed cerebellar diaschisis (CCD) is the remote effect of supratentorial dysfunction in the unilateral hemisphere inducing contralateral cerebellar hypometabolism, which could explain the weakened FC between cerebellum and cerebrum. The mechanism of CCD implies the involvement of cortico-ponto-cerebellar fibers. However, whether the focal change in the cerebellum is a form of Wallerian degeneration or the result of accumulation of AD pathological substrates in the cerebellum itself is still unknown. In this study, we did not find morphometric difference in any of the observed cerebral cortical regions across the three groups, also implicating altered FC could be due to the dysfunction of neurotransmitter or network connection, instead of being secondary to the atrophy.
In this study, we did not find significant differences in volumes of any cerebellar lobular in AD or aMCI group. Though previous VBM studies reported cerebellar gray matter loss, some studies reported no atrophy in AD and aMCI[13, 30–32]. One reason may be the choice of SUIT template in this study, which can improve the alignment of cerebellar structures. Another reason may be the relatively mild degree of cognitive decline in the AD group of this study (MMSE: 18.64 ± 3.39; MoCA: 14.11 ± 4.22; composite cognitive z score − 2.01 ± 1.01), which indicates an earlier stage of disease. Tabatabaei-Jafari et al. also found that cerebellar atrophy happened at the late stage of AD .
There are some limitations to this study. First, as a retrospective case-control study, the identification of the aMCI and AD groups was not based on pathological evidence, such as Aβ PET, which is still expensive for some patients in China. However, in this study, the prevalence of APOE ε4 carriers in AD and aMCI was 61.70% and 59.38%, respectively, which is similar to that of a previous study with large sample of Aβ biomarker positive individuals (66% in AD and 64% in MCI). Second, though we included the aMCI group as the prodromal stage of AD, this was still a cross-sectional study. In the future, longitudinal studies are needed to investigate the dynamic changes in the cerebellum throughout disease progression.